Project Summary/Abstract Chronic lymphocytic leukemia (CLL) is the most prevalent form of adult leukemia and is currently incurable. Two thirds of patients diagnosed with CLL are age 65 or older, and while fludarabine-based chemoimmunotherapy is standard initial therapy for younger patients, the optimal therapy for older patients is less clear. Both a randomized phase III study and a retrospective analysis of Cancer and Leukemia Group B trials showed no benefit to fludarabine over chlorambucil in the elderly population, while rituximab offers benefit irrespective of age. While recent data suggest that administration of the alkylator agent chloramubucil or benadmustine together with rituximab is feasible in this population, outcome is still suboptimal for what represents the largest population of CLL patients. Additionally, the relevance and impact of new biologic markers and minimal residual disease status predictive of response duration and survival in younger patients has not explored in the elderly. New therapies and validation of biomarkers identified in younger patients is therefore a high priority for research in this population. Ibrutinib is an orally bioavailable inhibitor of Bruton's Tyrosine Kinase (BTK), a critical kinase involved in B cell development and signaling through the B cell receptor (BCR). In a Phase Ib/II trial co-led by our group, the clinical activity associated with this agent has been extraordinary, with a 26 month PFS of 76% for patients with relapsed and refractory CLL, and 96% for elderly patients with previously untreated disease. This agent has been well tolerated as well with extended continuous dosing. Building upon our previous work, in this application we propose a Phase III clinical trial investigating ibrutinib alone or ibrutinib plus rituximab compared with standard therapy of bendamustine plus rituximab (BR) in older patients with previously untreated CLL. Correlative analyses of established and novel prognostic markers are proposed in an attempt to identify biomarkers associated with response and outcomes. The specific aims of this proposal are: 1: To perform a phase III clinical trial comparing a) ibrutinib, b) ibrutinib plus rituximab and c) BR in symptomatic CLL patients > 65 years to determine the therapy with highest response, PFS and OS. 2: To perform pharmacodynamic (PD) studies in this phase III study to determine whether traditional genomic features, select baseline BCR activation markers, and changes in miR marker expression over 1 month are predictive for best response, time to clinical response, PFS, and OS. 3: To evaluate longitudinal samples after ibrutinib therapy to evaluate the characteristics of persistent lymphocytes and determine whether changes in coding or non-coding RNAs, acquisition of mutations in BTK or PLC2, or presence of minimal residual disease at 9 or 24 months will be predictive of late relapse and PFS after ibrutinib-based therapies. It is anticipated that the clinical and laboratory findings derived from this trial will be transformative in how elderly CLL are treated and contribute significantly to the design of future clinical trials for these patients.